Methotrexate attenuates vascular inflammation through an adenosine- microRNA-dependent pathway

Dafeng Yang, Stefan Haemmig, Haoyang Zhou, Daniel Pérez-Cremades, Xinghui Sun, Lei Chen, Jie Li, Jorge Haneo-Mejia, Tianlun Yang, Ivana Hollan, Mark W. Feinberg, Peter Tontonoz

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Endothelial cell (EC) activation is an early hallmark in the pathogenesis of chronic vascular diseases. MicroRNA-181b (Mir181b) is an important anti-inflammatory mediator in the vascular endothelium affecting endotoxemia, atherosclerosis, and insulin resistance. Herein, we identify that the drug methotrexate (MTX) and its downstream metabolite adenosine exert anti- inflammatory effects in the vascular endothelium by targeting and activating Mir181b expression. Both systemic and endothelial-specific Mir181a2b2-deficient mice develop vascular inflammation, white adipose tissue (WAT) inflammation, and insulin resistance in a diet-induced obesity model. Moreover, MTX attenuated diet-induced WAT inflammation, insulin resistance, and EC activation in a Mir181a2b2-dependent manner. Mechanistically, MTX attenuated cytokine-induced EC activation through a unique adenosine-adenosine receptor A3-SMAD3/4-Mir181b signaling cascade. These findings establish an essential role of endothelial Mir181b in controlling vascular inflammation and that restoring Mir181b in ECs by high-dose MTX or adenosine signaling may provide a potential therapeutic opportunity for anti-inflammatory therapy.

Original languageEnglish (US)
Article numbere58064
Pages (from-to)1-19
Number of pages19
JournaleLife
Volume10
DOIs
StatePublished - Jan 2021
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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